This invention relates to the treatment of hepatoma, i.e., liver cancer.
The amphibian peptide bombesin, pGlu-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH.sub.2 [Anastasi et al., Experientia 27:166-167 (1971)], is closely related to the mammalian gastrin-releasing peptides (GRP), e.g., the porcine GRP, Ala-Pro-Val-Ser-Val-Gly-Gly-Gly-Thr-Val-Leu-Ala-Lys-Met-Tyr-Pro-Arg-Gly-As n-His-Trp-Ala-Val-Gly-His-Leu-Met-NH.sub.2 [McDonald et al., Biochem. Biophys. Res. Commun. 90:227-233 (1979)] and human GRP, Val-Pro-Leu-Pro-Ala-Gly-Gly-Gly-Thr-Val-Leu-Thr-Lys-Met-Tyr-Pro-Arg-Gly-As n-His-Trp-Ala-Val-Gly-His-Leu-Met-NH.sub.2.
Bombesin has been found to be a growth factor for a number of human cancer cell lines, including small-cell lung carcinoma (SCLC), and has been detected in human breast and prostate cancer [Haveman et al., eds. Recent Results in Cancer Research-Peptide Hormones in Lung Cancer, Springer-Verlag, New York (1986)]. A number of these cancers are known to secrete peptide hormones related to GRP or bombesin. Consequently, antagonists to bombesin have been proposed as agents for the treatment of these cancers.
Cuttitta et al. demonstrated that a specific monoclonal antibody to bombesin inhibited in vivo the growth of a human small-cell lung cancer cell line xenografted to nude mice (Cuttitta et al., Cancer Survey 4:707-727 (1985)). In 3T3 murine fibroblasts which are responsive to the mitotic effect of bombesin, Zachary and Rozengurt observed that a substance P antagonist (Spantide) acted as a bombesin antagonist [Zachary et al., Proc. Natl. Acad. Sci. (USA), 8:7616-7620 (1985)]. Heinz-Erian et al. replaced His at position 12 in bombesin with D-Phe and observed bombesin antagonist activity in dispersed acini from guinea pig pancreas [Heinz-Erian et al., Am. J. of Physiol. 252:G439-G442 (1987)]. Rivier reported work directed toward restricting the conformational freedom of the bioactive C-terminal decapeptide of bombesin by incorporating intramolecular disulfide bridges; however, Rivier mentioned that bombesin analogs with this modification failed to exhibit any antagonist activity [Rivier et al., Competitive Antagonists of Peptide Hormones, in Abstracts of the International Symposium on Bombesin-Like Peptides in Health and Disease, Rome, Italy (October, 1987)].
Bombesin exhibits both direct and indirect effects on the gastrointestinal tract, including the release of hormones and the stimulation of pancreatic, gastric, and intestinal secretion and of intestinal mobility. Gastrin and cholecystokinin (CCK) which are released by bombesin, have been shown to play a role in the maintenance of normal gastrointestinal mucosa as well as in augmenting growth of normal and neoplastic tissues. The growth of xenografted human colon and stomach carcinomas in nude mice has been stimulated by the administration of gastrin and later inhibited with the addition of secretin [Tanake et al., Tokaku J. Exp. Med. 148:459 (1986)] and the growth of MC-26 murine colon carcinoma, which possesses gastrin receptors is stimulated by pentagastrin [Winsett et al., Surgery 99:302, (1980)] and inhibited by proglumide, a gastrin-receptor antagonist [Beauchamp et al., Ann. Surg. 202:303 (1985)]. Bombesin has been found to act concurrently as both a trophic agent for normal host pancreas and a growth inhibitory agent in xenografted human pancreatic tumor tissue [Alexander et al., Pancreas 3:247 (1988)].
Uncommon Abbreviations
cyclohexyl-Ala=CHxAla= cyclohexyl alanine ##STR1## Cpa=para-chloro-phenylalanine HyPro=hydroxyproline PA1 .beta.-Nal=.beta.-naphthylalanine PA1 Sar=sarcosine PA1 F.sub.5 -Phe=penta-fluoro-phenylalanine PA1 A.sup.1 =the D- or L-isomer of any of pGlu, Nle, .alpha.-aminobutyric acid, Ala, Val, Gln, Asn, Leu, Ile, p-X-Phe (where X.dbd.H, F, Cl, Br, NO.sub.2, OH, or CH.sub.3), Asp, Glu, F.sub.5 -Phe, Trp, .beta.-Nal, Cys, Lys, or is deleted; PA1 A.sup.2 =Gly, D- or L-isomer of any of pGlu, Ala, Val, Gln, Asn, Leu, Ile, p-X-Phe (where X.dbd.H, F, Cl, Br, NO.sub.2, OH, or CH.sub.3), Trp, .beta.-Nal, Asp, Glu, His, 1-methyl-His, 3-methyl-His, Cys, Lys, or is deleted; PA1 A.sup.3 =the D- or L-isomer of any of p-X-Phe (where X.dbd.H, F, Cl, Br, NO.sub.2, OH, or CH.sub.3), .beta.-Nal, or Trp; PA1 A.sup.4 =Ala, Val, Gln, Asn, Gly, Leu, Ile, Nle, .alpha.-aminobutyric acid, p-X-phe (where X.dbd.H, F, Cl, Br, NO.sub.2, OH, or CH.sub.3), Trp, or .beta.-Nal; PA1 A.sup.5 =Gln, Asn, Gly, Ala, Leu, Ile, Nle, .alpha.-aminobutyric acid, Val, p-X-Phe (where X.dbd.H, F, Cl, Br, NO.sub.2, OH, or CH.sub.3), Trp, Thr, or .beta.-Nal; PA1 A.sup.6 =Sar, Gly or the D-isomer of any Ala, N-methyl-Ala, Val, Gln, Asn, Leu,-Ile, p-X-Phe (where X.dbd.H, F, Cl, Br, NO.sub.2, OH, or CH.sub.3), Trp, Cys, .beta.-Nal, or is deleted; PA1 A.sup.7 =1-methyl-His, 3-methyl-His, His, Lys, Asp, or Glu; PA1 A.sup.8 =Leu, Ile, Val, Nle, .alpha.-aminobutyric acid, Trp, Thr, .beta.-Nal, Lys, Asp, Glu, or Cys; PA1 A.sup.9 =L-isomer of any of Met, Met-oxide, Leu, Ile, Nle, .alpha.-aminobutyric acid, p-X-Phe (where X.dbd.H, F, Cl, Br, NO.sub.2, OH, or CH.sub.3), Trp, .beta.-Nal, CHxAla, Cys, or is deleted; PA1 A.sup.0 =pGlu, Gly, D-Phe, or is deleted; PA1 A.sup.1 =pGlu, D-Phe, D-Ala, D-.beta.-Nal, D-Cpa, D-Asn, Cys, or is deleted; PA1 A.sup.2 =pGlu, Asn, Gln, His, 1-methyl-His, 3-methyl-His, Cys, or is deleted; PA1 A.sup.3 =Trp; PA1 A.sup.4 =Ala; PA1 A.sup.5 =Val; PA1 A.sup.6 =Sar, Gly, D-Phe, or D-Ala; PA1 A.sup.7 =His; PA1 A.sup.8 =Leu, or Cys; PA1 A.sup.9 =L-isomer of any of Met, Leu, Ile, Nle, Phe, or Cys. PA1 A.sup.1 =the D- or L-isomer of any of pGlu, Nle, .alpha.-aminobutyric acid, or the D-isomer of any of Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X.dbd.F, Cl, Br, NO.sub.2, OH, H, or CH.sub.3), F.sub.5 -Phe, Trp, Cys, or .beta.-Nal, or is deleted; PA1 A.sup.2 =pGlu, Gly, Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X.dbd.F, Cl, Br, NO.sub.2, OH, H, or CH.sub.3), Trp, Cys, .beta.-Nal, His, 1-methyl-His, or 3-methyl-His; PA1 A.sup.4 =Ala, Val, Gln, Asn, Gly, Leu, Ile, Nle, .alpha.-aminobutyric acid, Met, p-X-Phe (where X.dbd.F, Cl, Br, NO.sub.2, OH, H, or CH.sub.3), Trp, Cys, or .beta.-Nal; PA1 A.sup.5 =Gln, Asn, Gly, Ala, Leu, Ile, Nle, .alpha.-aminobutyric acid, Met, Val, p-X-Phe (where X.dbd.F, Cl, Br, OH, H, or CH.sub.3), Trp, Thr, or .beta.-Nal; PA1 A.sup.6 =Sar, Gly, or the D-isomer of any of Ala, N-methyl-Ala, Val, Gln, Asn, Leu, Ile, Net, p-X-Phe (where X.dbd.F, Cl, Br, NO.sub.2, OH, H, or CH.sub.3), Trp, Cys, or .beta.-Nal; PA1 A.sup.7 =1-methyl-His, 3-methyl-His, or His; PA1 A.sup.0 =Gly, D-Phe, or is deleted; PA1 A.sup.1 =p-Glu, D-Phe, D-Ala, D-.beta.-Nal, D-Cpa, or D-Asn; PA1 A.sup.2 =Gln, His, 1-methyl-His, or 3-methyl-His; PA1 A.sup.4 =Ala; PA1 A.sup.5 =Val; PA1 A.sup.6 =Sar, Gly, D-Phe, or D-Ala; PA1 A.sup.7 =His; PA1 D-Cpa-Gln-Trp-Ala-Val-Gly-His-Leu-.psi.[CH.sub.2 NH]-Phe-NH.sub.2 (code named BIM-26159), and PA1 D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-.psi.[CH.sub.2 NH]-Cpa-NH.sub.2 (code named BIM-26189). PA1 D-Phe-Gln-Trp-Ala-Val-N-methyl-D-Ala-His-Leu-methylester, and PA1 D-F.sub.5 -Phe-Gln-Trp-Ala-Val-D-Ala-His-Leu-methylester.
Sta (statine)=(3S, 4S)-4-amino-3-hydroxy-6-methylheptanoic acid, and has the chemical structure ##STR2## AHPPA=(3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid, and has the chemical structure ##STR3## ACHPA=(3S, 4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid and has the chemical structure ##STR4##
R=right (D) configuration; S=left (L) configuration; and racemate=equal mix of R and S.
1-methyl-His; 3-methyl-His=methyl (CH.sub.3) group on nitrogen at positions 1 or 3 of Histidine ##STR5## Met-oxide=methionine oxide ##STR6##
The identifying group of an .alpha.-amino acid (for case of pyroglutamate, see below) refers to the atom or group of atoms, other than the .alpha.-carbonyl carbon atom, the .alpha.-amino nitrogen atom, or the H atom, bound to the asymmetric .alpha.-carbon atom. To illustrate by examples, the identifying group of alanine is CH.sub.3, the identifying group of valine is (CH.sub.3).sub.2 CH, the identifying group of lysine is H.sub.3 N.sup.+ (CH.sub.2).sub.4 and the identifying group of phenylalanine is (C.sub.6 H.sub.6)CH.sub.2. The identifying group of a .beta.- or .gamma.-amino acid is the analogous atom or group of atoms bound to the .beta.- or the .gamma.-carbon atom, respectively. Where not specified, the identifying group may be of an .alpha., .beta., or .gamma. amino acid. In the case of pyroglutamate the identifying group consists of --NH--CO--CH.sub.2 --CH.sub.2 --.